Under past support, we have demonstrated the physics,mathematics, and instrumentation for near-infrared fluorescence enhanced (tomographic) optical imaging through centimeters of tissue-mimicking phantoms. In this competitive renewal we seek to translate fluorescence enhanced optical imaging for clinical cancer diagnostic imaging for sentinel lymph node mapping in patients. Herein, we gather a multidisciplinary team from Photon Migration Laboratory at Texas A&M University; The University of Texas M.D. Anderson Cancer Center, the University of Arizona's Center for Gamma Ray Imaging and the University of Texas at Austin's Institute for Computational Engineering and Science in order to: (1) improve upon existing frequency-domain photon migration (FDPM) imaging systems by reducing the noise floor and improving upon accuracy and precision of measurements required for clinical tomographic measurements using low-dose non-specific indocyanine green (ICG) and a molecularly targeting NIR dye; (2) utilize novel "state-of-the-art" adaptive finite element methods in forward and inverse imaging solutions in order to improve the resolution of reconstructed images showing the depth of location and small size of sentinel lymph nodes and molecularly targeted, positive lymph nodes in breast cancer patients; (3) implement diagnostic cancer imaging using a developed clinical scanner with ICG or targeting NIR dyes in order to perform 2-D optical lymphography for comparison to nuclear lymphoscintigraphy and to perform 3-D tomography for determining the depth of sentinel nodes using adaptive finite element based tomographic algorithms and (4) implement diagnostic cancer imaging using the developed scanner with NIR dyes conjugated with the epidermal growth factor peptide as well as with a radiotracer for reporting positive lymph nodes of cancer patients with primary breast tumors which express the epidermal growth factor receptor in order to perform 2-D optical lymphography and 3-D tomography for reporting of positive nodes; and (5) apply image objective assessment of imaging quality tools to drive hardware and software improvements as well as to evaluate measurements and tomographic reconstructions. If successful, this project will provide the first clinical demonstration of fluorescence enhanced optical imaging in human patients with molecularly targeting NIR excitable contrast agents.